Abstract Infections are commonly reported onboard spacecraft, but the mechanisms responsible are not well understood. Both tissue-specific and systemic (bone marrow) responses have been implicated. Systems to model and prevent or treat infections in microgravity are important components of mission planning. Our underlying hypothesis is that Immunosuppression in microgravity is due to loss of both local and systemic responses to bacteria that can be modeled and are susceptible to therapy. Based on extensive preliminary data we propose 2 new models to address potential mechanisms of compromised immunity on the ISS. In the UG3 Phase we will develop and refine: 1.An airway-on-a-chip that incorporates a 3-layer topology with both airway and vascular access is used to probe intrinsic susceptibility to airway infections from Pseudomonas aeruginosa in microgravity 2. A bone marrow-on-a-chip that will be used to test mobilization of neutrophils from the marrow in response to physiologic modifiers that induce neutrophil release from marrow. Once validated, these devices will be packaged in remotely- controllable modules that will be sent to the ISS for deployment in microgravity, while control devices subject to unit gravity will be mimicked in a terrestrial facility. Our implementation partners, STaARS ans Space Pharma will be intimately involved in the development and hardening of the tissues on chips in a space-ready fashion, and in establishment of remote control and real-time data recovery from ISS. After successful data gathering and post-flight analysis from the UH3 phase, we will design and implement an integrated device in the UH3 Phase. We propose to interconnect the devices these devices so as to test the interaction between these tissues that controls innate immunity. Similarly, once validated and shown to reflect the physiological principles that control recruitment of innate immune cells to infected organs, the devices will be packaged and deployed to the ISS for a second analysis in microgravity. The goals of the project are to test feasibility of microfluidic devices to reflect physiological principles while being delivered to orbit; and to provide access to modular components that can be interconnected to understand the integrated behavior of complex human responses.